Factors Influencing a Favorable Outcome for RFA of Huge Benign Thyroid Nodules: Preliminary Results and Short-Term Evaluation

Objective This study aimed to investigate potentially favorable factors influencing the therapeutic success of radiofrequency ablation (RFA) of huge benign thyroid nodules (BTNs) (volume >100 ml) and to evaluate the feasibility of RFA as an alternative treatment modality for patients unable or unwilling to undergo surgery. Methods This retrospective study evaluated a total of 868 patients, of which 22 patients had huge BTNs who underwent ultrasound-guided moving shot RFA treatment between May 2017 and January 2022. The huge BTNs were categorized into two groups according to a post-RFA treatment volume reduction ratio (VRR) of >80% and <80% at 6 months. Factors influencing these huge BTNs were reviewed, analyzed, and correlated with treatment effectiveness between the two groups. Results The factors influencing an effective VRR included huge BTNs located on the left side (OR 7.875, p = 0.03), predominant solid/spongiform nodules (OR 7.875, p = 0.03), and higher initial ablation rate (IAR) (p = 0.028). Multivariable logistic regression revealed predominant solid/spongiform nodule and the higher IAR were associated with the advanced VRR. Conclusion RFA was effective at decreasing the volume of huge BTNs with an acceptable complication rate. The BTN characteristics correlated with a better VRR at the 6-month short-term follow-up were predominant solid/spongiform BTNs and those with the first time ablation treatment initial ablation rate. Nevertheless, regarding the higher regrowth rate of these groups of patients who may need to be treated more times, RFA can only be a feasible alternative treatment modality for patients unable or unwilling to undergo operation.


Introduction
Tyroid nodular disease is a common endocrine disorder, the discovery and treatment of which have become more successful due to the application of neck ultrasound scanning in clinical practice.As thyroid surgery is associated with various general anesthesia risks, operation scar, and hypoparathyroidism, minimally invasive image-guided ablation has been suggested as a viable alternative treatment option [1].In recent years, a growing number of studies have investigated the treatment of benign thyroid nodules (BTNs) with minimally invasive image-guided thermal ablation, including radiofrequency ablation (RFA), microwave ablation, laser ablation (LA), and high-intensity-focus ultrasound (HIFU) [1].According to several guidelines and consensus statements, RFA may be used as a frst-line treatment or as an alternative to surgery for patients with solid nonfunctioning thyroid nodules [2][3][4][5][6][7][8][9][10][11].Furthermore, RFA treatment of BTNs can achieve a signifcant volume reduction ratio (VRR) with symptom and cosmetic improvements observed between 1 and 6 months, with a notably low recurrence rate at 2 years [12][13][14].Compared to surgical resection, the relatively low complication rate and minimal scar [13,15] have made RFA a viable treatment modality for general-sized BTNs in patients unable or unwilling to undergo surgery [16].
Although no defnitive criteria regarding nodule size or volume have been established for thyroid RFA treatment [3], it has been reported that patients presenting with BTNs exceeding 2 cm in diameter sufer from a variety of symptoms, clinical concerns, and cosmetic issues [17].Meanwhile, relevant literature addressing the treatment of huge BTNs with RFA is lacking.A number of previous studies have defned large BTNs as presenting with a volume >30 ml [18][19][20][21][22][23], the largest of which may reach a volume of 104.5 ml [23].In light of this, we here defne BTNs with a volume >100 ml as huge BTNs.Both surgery and RFA are efective methods for treating nodule-related clinical issues.Surgery remains the standard treatment for patients with symptomatic large BTNs as surgery can completely remedy the compressive symptoms and harvest the whole huge BTN specimen to make sure the fnal pathology is benign.In contrast, RFA does not have the efect to resolve the BTNs' symptoms entirely [15,[24][25][26].Nonetheless, the elevated risks associated with anesthesia may be unacceptable for patients presenting with certain comorbidities.RFA is thus a common alternative treatment for moderately sized BTNs [25,27].However, studies have yet to investigate the factors afecting the successful RFA treatment of large BTNs.Although several previous studies have indeed investigated large BTNs, the relatively long initial ablation time, immediate and delayed complication rates, VRR, initial ablation rate (IAR), number of RFA sessions required for a complete treatment, long-term nodular recurrence rate, and the association with factors infuencing therapeutic success are issues warranting further exploration [13,[28][29][30].Determining if predictive criteria of the safety and efectiveness of RFA exist, despite the fact that we forecast the group of patients with a high risk of requiring more treatment sessions, was of special interest in this study.We thus investigated the potential factors infuencing the therapeutic success of RFA for huge BTNs (volume >100 ml) and evaluated the feasibility of RFA as an alternative treatment modality for patients with a high risk of anesthesia or concern of postoperative scar and lifetime thyroxine supplementation due to hypoparathyroidism.

Patients.
From May 2017 to January 2022, a total of 868 patients underwent RFA for BTNs treatment at the Kaohsiung Chang Gung Memorial Hospital Medical Center in Taiwan, of which 29 patients presented with a BTN volume >100 ml (defned as huge BTNs).Patients with huge BTNs presented with cosmetic issues, nodule-related problems/ symptoms, and sought treatment options aside from surgery.Patients had visited otolaryngologists, internal medicine physicians, or surgeons and were subsequently transferred to the Radiology Diagnostic Department for sonography to evaluate the thyroid nodular composition.As demonstrated earlier in the research by Kim and Lin et al. [3,22], Ultrasound-guided core needle biopsy (CNB) or fne-needle aspiration cytology (FNAC) was performed for the benign nature of the nodules confrmation.At least a single benign cytological result or two benign cytological results with an acceptable ultrasound characteristic was considered at low risk of malignancy.
In our study, all patients were without contraindications to surgery; however, these patients expressed concerns regarding postoperational complications, side efects, lifetime thyroxine supplementation due to thyroid functional changes, unpleasant scarring, or anesthesia risk.Te demographic data for all patients were recorded, and their follow-up outcomes were analyzed retrospectively.Te criteria for patient enrollment in the study were (1) age above 20 years, (2) symptomatic and/or cosmetic problems, (3) volume of thyroid nodule >100 ml, (4) solid or predominant solid/spongiform nodule, (5) cytological confrmation of benign nodule status by FNAC or CNB, ( 6) thyrotropin (TSH) and serum thyroid hormone (free T3 and free T4) levels within normal range, and (7) acceptance of RFA treatment.Te exclusion criteria were patients with pathological results indicating malignancy or follicular neoplasm and patients without adequate follow-up sessions (at least 6 months).Excluded by exclusion criteria, 7 patients were excluded due to repetitive data (n = 4), pathology study revealed hemangioma (n = 1) and papillary carcinoma (n = 1), and inadequate follow-up time (n = 1).Finally, 22 patients presenting with huge BTNs who underwent RFA treatment were enrolled in the study (Figure 1).Te retrospective study was approved by the Chang Gung Medical Foundation Institutional Review Board/IRB No. 202201363B0, which waived the obtaining informed consent requirement.

Preablation Status Evaluation and Preparation.
At each visit to our Radiology Department, the thyroid function and nodule-related cosmetic score/symptom score were recorded.As shown previously in the study of Lin et al. [22] Patients will fll out a questionnaire which recorded as nodule-related symptom score focused on fve clinical symptoms: cough, difculty swallowing, compression, voice change, and pain.We allocated 1 point for each positive symptom; the symptom scores ranged from 0 to 5. Te cosmetic score is obtained using the following scale: 0, no palpable or visible mass; 1, palpable mass but not visible; 2, only visible when swallowing; and 3, an easily visible mass [3].In addition, sonography was used to evaluate the echogenicity of the thyroid nodule and measure the tumors' 3 orthogonal diameters (the largest diameter with two perpendicular diameters).CT/MRI will also be used to confrm these huge BTNs extend below the sternal notch or not and make sure the three orthogonal diameters of the     1).Te statistical results by logistic regression for odds ratio revealed OR 1.111; 95% CI 1.009-1.234,p � 0.01.

Volume and VRR.
Te BTN volumes of baseline and respective changes are presented in Table 3. Prior to the ablation procedure, the overall median BTN volume was 140.5 (114.6,183.2) ml.After the ablation procedure, the 1-, 3-, and 6-month median BTN volumes were 59.9 (41.2, 68.1) ml, 44.6 (23.6, 57.0) ml, and 25.0 (17.2, 42.9) ml, respectively.Te results showed that the overall nodular volume reduced signifcantly after RFA treatment over time (time efect, p < 0.001).Te volume in each VRR group also showed signifcant reductions over time (time efect, p < 0.001).Although there was no signifcant diference (p � 0.797) between the baseline nodular volumes of the two groups, the volume at the 6-month follow-up showed a considerable diference between the 2 groups (group * time efect, p � 0.052).

Subsequent RFA Data and Multivariable Logistic Regression Analysis.
Te subsequent RFA data (total RFA time, IAR) and multivariable linear regression analysis are performed.c For each positive symptom, we allocated one point; therefore, the symptom scores ranged from 0 to 5. d Te cosmetic score was obtained using the following scale: 0, no visible or palpable mass; 1, not visible but palpable mass; 2, visible when swallowing only; 3, an easily visible mass [3].e Intact parathyroid hormone.Tree variables (BTN location, echogenicity (solid or predominant solid/spongiform nodule), and the IAR) showing statistical signifcance were coupled with the total number of RFA sessions and entered into a stepwise multivariable logistic regression analysis which revealed statistical signifcance (F = 3.852, p = 0.026).Te analysis revealed that BTN echogenicity (standardized beta coeffcients = 0.485, p = 0.047) and the IAR (standardized beta coefcients = 0.774, p = 0.004) were associated with the VRR.Te regression analysis further revealed that BTN location (p = −0.25)and total number of RFA sessions (p = −0.112)were without signifcant diference.Te regression model provides characteristics of normality (Shapiro-Wilk test p = 0.179), autocorrelation (Durbin-Watson = 2.594 which greater than dU = 1.543, alpha = 0.01 and dU = 1.797, alpha = 0.05) [33], and low collinearity (all variables' VIF <10 and condition index = 19.348).

Discussion
Tis retrospective study indicates that the factors infuencing a favorable RFA treatment outcome of huge BTNs were more efective in the post-RFA 6-month VRR >80% group than those in the post-RFA 6-month VRR <80% group, while presenting an acceptable complication rate.Furthermore, the treatment efectiveness of RFA for huge BTNs was notable, with a mean VRR of 82.4 (66.6, 85.3)% at the 6month follow-up.In addition, we reveal that huge BTNs  International Journal of Endocrinology characteristics including BTNs located on the left side (p � 0.03), predominant solid/spongiform BTNs (p � 0.03), and higher IAR (p � 0.028) are factors infuencing a favorable VRR.Te median RFA sessions count was 1.5 (1.0, 2.25).Additionally, the regression analysis model revealed that while predominant solid/spongiform BTNs and a higher IAR are associated with a superior VRR in patients with huge BTNs, the IAR is indeed a more infuential factor than predominant solid/spongiform echogenicity.Tese fndings may help clinicians to better educate and manage patients' expectations prior to RFA treatment and ofer patients concerned about postoperational scarring or the risk of anesthesia a safe treatment option to preserve the thyroid.
Compared to 6-month post-RFA VRR, symptom, and cosmetic outcomes, the immediate short-term efects on huge BTNs after treatment are not inferior to average size BTNs.Previous studies have reported a VRR range of 52.1% to 86.1% at 6 months postablation for average-sized BTNs [34].We similarly recorded a median VRR of 82.4% for huge BTNs at the 6-month follow-up.Because of the difculty in achieving high IAR and higher rates of regrowth, the patients in this study received 1.5 RFA treatments on average with further treatments.However, future treatments are usually needed [14,18,19,35].In comparison to a previous study of large BTNs (defned as >30 ml, n � 44, 6-month post-RFA symptom, and cosmetic score: 0.05 ± 0.2 and 1.3 ± 1.0, respectively), our symptom score at 6 months post-RFA exhibits superior improvement for the huge BTNs [22].In several other papers on large nodules, though not as large as in this study, the baseline symptom score was much higher; the nodules in these studies reduced after treatment but not to such low symptom score values [22,36,37].While this may arise from the fact that symptom and cosmetic scores are subjective factors, the tremendous shrinkage of the huge BTNs may account for great remission feedback among patients.Additionally, the patients reported decreased selfconsciousness about their thyroid issues.Meanwhile, our results also indicate that subsequent RFA procedures may be necessary to achieve complete resolution of cosmetic issues, despite greater cosmetic score improvement at 6 months post-RFA than in previous studies [5,22].Tis comparison is not appropriate, however, with studies where the volume reduction was equally signifcant but where the nodules were subject to a single treatment.Although patients with huge BTNs can receive thyroidectomy, RFA is not always the frst priority treatment due to its high ratio of regrowth as well as cost and quality of life concerns.
Te IAR was revealed to be a major factor infuencing the VRR of huge BTNs in our study.Te VRR >80% group exhibited a better IAR than the VRR <80% group, demonstrating that the IAR is a quantitative indicator of the performance efcacy of the RFA procedure and is highly correlated with the VRR [30,38].Some studies suggest that smaller or medium-sized nodules have better VRR than large-sized BTNs in long-term efects because of better IAR [18,19,35].Chen et al. reported no diference in terms of nodule volume and achieved an average IAR of 99.67% [30], although their study did not include such huge BTNs as are investigated here.Indeed, it is challenging to reach a 70% IAR for huge BTNs due to issues related to tumor size, device limitations, and technical factors [39].Te nodules in our study have undergone more than one retreatment over 6 months (1.5 treatments on average).Tis likely results from the nodules not reaching a sufciently high IAR, in line with previous work that found more treatments are needed for larger-size BTNs [14].One particular issue to achieving a high IAR lies with the residual margin [30].Although leaving a relatively large margin is safe from the perspective of complications, leaving too much margin may lead to therapeutic failure [38].It is important to treat the margin completely in order to prevent the regrowth of marginal viable tissue around the central ablated tissue [30,40].Hence, subjecting the margin of huge BTNs to additional treatment is critical, which may require the patient to accept additional sessions of RFA [14].Considering the higher regrowth rate among these patients, for whom repeat treatment is likely, compared to those who were treated only once (for smaller BTNs) or surgically operated on, RFA can only be an alternative treatment [35,41].
Another factor identifed in our study infuencing a favorable treatment outcome was echogenicity.Previous studies have reported that <30 ml mixed cystic BTNs showed a signifcantly better volume reduction response than predominant solid/spongiform BTNs after RFA treatment [4,34].Specifcally, one study reported a 6 to 9 month post-RFA residual BTN volume of 21.9% ± 16.5% in a mixed cystic group and 50.0%± 31.4% in a predominant solid/spongiform group [34].Tis may be attributed to the homogeneous conduction of heat and the absence of a heat sink efect [42].Given that cystic content, necrosis, and hemorrhage can produce heterogeneous echogenicity [43], predominant solid/spongiform echogenicity in the BTNs studied here (>100 ml) may also have superior heat conduction and a less limiting heat sink efect.On a procedural note, as the predominant solid/ spongiform echogenicity exhibited by huge BTNs can provide a clearer RFA target and BTN border, the operator may have the opportunity to ablate the huge BTNs in a more detailed manner.
We also observe that huge BTNs located on the left side have better VRR than those on the right after odds ratio analysis.We presume the relative ease of the operator using their dominant hand to manipulate the RFA needle while performing treatment at the patient's cephalic site; thus, as the operator in this study was right-handed, they could handle the sonography probe with the left hand and the RFA needle with the right hand.In this way, the operator could ablate the huge BTNs in a detailed manner to treat the margin more completely, which could lead to improved IAR.However, further regression analysis did not reveal this factor to be signifcant.Te reduced number of nodules enrolled in the two groups and operator-dependent factors should also be considered.
Te energy delivered per nodular volume factor showed no statistical diference between the groups of huge BTNs.International Journal of Endocrinology Previous studies have suggested that the energy delivered per volume was independently predictive of volume reduction [22,39,44].Deandrea et al. reported energy superior to 2670 J/ml could facilitate an optimized treatment efcacy, with a VRR >50% in 99% of cases [44].Furthermore, studies have reported the best volumetric response to RFA in small (<15 ml) and medium (15-30 ml) nodules, where the energy delivered was higher [22,44]; nevertheless, such a correlation has not been found in large BTNs [22].Considering huge BTNs present a more complicated nodular pattern, such as intense vascularity, microcystic composition, and soft stifness, and further study is warranted to investigate the correlation.
Te complication rate associated with RFA treatment of huge BTNs in this study was acceptable, in line with fndings of previous studies and without incidence of life-threatening complications [45].Indeed, surgery remains the gold standard for treatment of large-size thyroid nodules or those presenting with compressive symptoms or nodular growth, as it can completely remedy the compressive symptoms caused by nodular volume [25,46,47].It must be noted that several studies have revealed common complications specifc to thyroidectomy: temporary vocal paralysis, which occurs in 5% to 11% of cases and may be permanent in 1% to 3.5% of cases; temporary hypoparathyroidism, which occurs in 20% to 30% of cases and may be permanent in 1% to 4% of cases [48][49][50]; and postoperative hematoma, which occurs in 1.9% to 14.3% of cases [51].No patient in this study had hypoparathyroidism, postoperative hematoma, or other permanent complications, with a complication rate not higher than that of thyroidectomy.More specifcally, 2 patients (9.1%) had temporary vocal paralysis, accepted immediate steroid IV injection, and were transferred to the ENT Department for follow-up, recovering within 2 hours and 3 months, respectively, without further hospitalization.Potential mechanisms associated with vocal cord paralysis include nerve stretching during the RFA procedure, hemorrhage [52], lidocaine injection, and RFA-induced thermal injury rather than permanent nerve damage [45,[53][54][55][56].In addition, 1 patient (4.5%) sufered a nodular rupture, presenting with redness of the neck region accompanied with neck pain 2 weeks following the RFA treatment.After receiving debridement and antibiotic treatment, the patient recovered within 3 weeks.Post-RFA BTN rupture may result from tearing of the tumor wall and thyroid capsule at a weak point [29,39,45,[56][57][58].Other potential causes of nodule rupture include large nodular size, location near the anterior thyroid capsule, solid component, excessive RFA power, and longer ablation time [22].In RFA treatment of BTNs, lifethreatening complications including injury to the trachea and esophageal rupture have not been reported [59].Taken together, this study reveals that the complication rate associated with RFA treatment of huge BTNs is not higher than that of surgery, while further investigation is necessary to evaluate the correlation between nodular size and the aforementioned complications.Besides, a recent study demonstrated a small risk of malignancy in thyroid nodules >4 cm despite benign FNA results [60].Following the 2021 Asian and 2020 European guidelines of RFA in BTNs, at least two FNAC or core needle biopsy (CNB) was performed to confrm the nodule's benign nature and informed the patients of the risk of malignancy [1,5].In our study, the patients were unwilling to have surgery and fully understood the small potential malignant result.All in all, the surgery is the gold standard for this group of patients, and RFA is a modality treatment for patients unable or unwilling to the surgery.
Tis study has several limitations.First, as a retrospective single-center study, uncontrolled bias could have been introduced.Second, this study included a small group of patients and a relatively short-term following-up period.More patients and further long-term analysis are needed.Tird, the treatment aims are diferent from usual-sized nodules and other thermoablation techniques, and there are more than 50% of them who were subjected to several treatment sessions.It is hard to compare the efect with previous studies.Fourth, as RFA is an operator-dependent treatment, hardware, software, and experience may infuence the ablation results.Fifth, huge BTNs exhibit more variable and ill-defned nodular margins, and thus nodule location close to the danger triangle area or carotid artery, prominent peripheral vascularization [44], macrocalcifcations, periprocedural tissue temperature [58], and peripheral, internal vascularity are all factors potentially infuencing VRR diferences.Further prospective studies focused on elucidating these factors are recommended.

Conclusions
Tis study demonstrates that RFA is an efective alternative treatment modality with an acceptable complication rate for patients presenting with huge BTNs who are unable or unwilling to undergo surgery.Critically, RFA treatment of huge BTNs presents unique challenges to patients and physicians, wherein incomplete resolution or relapse of symptomatic or cosmetic issues may occur, and further treatment sessions are usually needed.It is thus recommended that physicians discuss these risks with patients during the treatment decision-making process.and CKC performed the statistical analysis.CH and SY wrote the frst draft of the manuscript.SD, PL, and CKW wrote sections of the manuscript.All authors contributed to manuscript's signifcant scientifc contribution, revision, read, and approved the submitted version.

Figure 3 :
Figure 3: Te red dots illustrate the nodule size from Figure 2.

Table 1 :
Te 22 possible infuence factors of huge BTNs based on the post-RFA VRR.

Table 2 :
Post-RFA complications for two groups.
session; additionally, 6/22 patients underwent a total of 2 RFA sessions and 5/22 patients underwent a total of 3 RFA sessions.Te median total number of RFA sessions was 1.5 (1.0, 2.25).3 patients in VRR >80% group underwent a total of 2 RFA sessions, 3 patients in VRR <80% group underwent a total of 2 RFA sessions, and 5 patients underwent a total of 3 RFA sessions.

Table 3 :
Te 1-, 3-, and 6-month follow-up median volume and volume reduction ratio (%) and median symptoms and cosmetic score at baseline and at 6 months post-RFA treatment.